Despite the lack of guidance available for practitioners, extensive polypharmacy has become the primary method of treating patients with severe and chronic mood, anxiety, psychotic or behavioral disorders. This ground-breaking new book provides an overview of psychopharmacology knowledge and decision-making strategies, integrating findings from evidence-based trials with real-world clinical presentations. It adopts the approach and mind-set of a clinical investigator and reveals how prescribers can practice 'bespoke psychopharmacology', tailoring care to the individualized needs of patients.
Core Concepts of Good Psychopharmacology
It is a capital mistake to theorize before you have all the evidence. It biases the judgment.
▢ Recognize cause-and-effect relationships in psychopharmacology
▢ Adopt an investigative “forensic” mindset to assess psychopathology and match symptom constellations to the best-fitting treatment
▢ Recognize levels of empirical evidence that support any given pharmacotherapy intervention before making conclusions about generalizability or likelihood of a meaningful effect
▢ Know appropriate benchmarks and timepoints for judging if and when to alter medication dosages or otherwise adjust a treatment regimen
▢ Focus on putative drug mechanisms, underlying dysfunction of neural networks, and findings from empirical trials, rather than simply on whether or not a drug carries “on”- or “off”-label regulatory agency approval
▢ Always strive to define as clearly as possible the intended symptom targets of any treatment
When someone takes a medication for depression, anxiety, or any other psychiatric problem, how do they or the prescriber know for certain if they are actually better or worse? And in either instance, whether to credit (or blame) the drug? If depression gets better 4–6 weeks after taking an antidepressant, how confidently should we attribute improvement to the drug rather than to serendipity? What if the patient gets better only after 14–16 weeks – is that too far in time to distinguish a plausible drug effect from spontaneous remission? Or, when can we assume the outcome was still a likely drug effect, given that an adequate trial may take longer in some people than others? If they felt better in just a few days, is that evidence of a placebo effect? Or, if they became suicidal or agitated, how do we know if that reflects an adverse drug effect or simply a worsening due to the natural course of illness?
Cause-and-effect relationships are often presumed throughout medicine, even though drugs can have unpredictable effects and despite the fact that numerous biological, psychological, and environmental factors contribute to outcomes. Causality is all the more difficult to infer when a patient receives more than one treatment (as occurs not infrequently in real-world practice), or other psychoactive factors complicate the picture (such as alcohol or drug abuse, or sleep deprivation, or life catastrophes). How do we account for subjective versus objective signs of improvement, while considering the effects of time alone, placebo and nocebo effects, the therapeutic alliance, variable pharmacodynamic drug effects, pharmacokinetic interactions, comorbidities, dosing effects, and – not of least importance – whether the prescribed treatment is even appropriate to the presenting ailment?
Psychiatric drug effects are remarkably varied and unreliable. Contrast the poorly predictable outcome of giving someone a selective serotonin reuptake inhibitor (SSRI) for depression versus the relative certainty of administering general anesthesia for surgery. No anesthesiologist ever tells their patient they have about a 6 in 10 chance that the medication they are about to receive will make them go to sleep. Admittedly, the sleep-inducing effects of halothane produce a safer and more reliable result than having the patient inhale an ether-soaked rag (and halothane is no picnic if the patient has an unrecognized susceptibility to malignant hyperthermia). But can psychotropic drugs ever deliver the same kind of causal precision and reliability for producing an intended effect as occurs with anesthesia induction?
Causal inferences are vulnerable to the so-called post hoc ergo propter hoc or logical fallacy phenomenon, in which one concludes that whatever happens after a temporal sequence of events (e.g., taking a medication and then feeling better or worse) necessarily reflects cause and effect. The hazards of spurious associations and outright superstitions abound in psychopharmacology, where both doctor and patient perceptions about cognitive and emotional processing are colored by pre-existing beliefs and expectations. More scientifically, causal relationships in medicine are sometimes judged according to criteria such as those described by Hill (1965), as summarized in Box 1.1.
Just because an effect temporally follows an intervention does not necessarily demonstrate a cause-and-effect relationship.
|Strength of apparent association||Bigger associations = bigger effects|
|Consistency (reproducibility)||Consistent findings across settings = more likely a true association|
|Specificity||Specific population with specific disease, unlikely other explanations|
|Temporality||Exposure precedes outcome|
|Dose effect||Greater exposure imparts greater risk (but, there could also be a necessary threshold level of exposure)|
|Plausibility||Is there a plausible pharmacological mechanism?|
|Coherence||An explanation for likely association makes sense given existing knowledge|
|Experiment||Experimental interventions can alter the conditions|
|Alternate explanations||Do other likely explanations exist for the observed association?|
Additionally, one must consider the presence of confounding factors or potential biases (e.g., different susceptibilities or degrees of responsivity/nonresponsivity across individuals – as when antibiotics may be less effective in someone who is immunosuppressed, or poorly adherent, or has a superinfection), and the impact of other simultaneous interventions that could interact and alter efficacy or tolerability.
Prescribers and patients do not necessarily look for the same tangible results when judging pharmacotherapy effects. For example, surveys show that depressed patients’ main therapeutic goals are to feel that life is meaningful and enjoyable, and to feel satisfied with themselves. Doctors, by contrast, set out to eliminate negative feelings such as depression, despair, or hopelessness, and help patients regain interest or pleasure from doing things. These differences may seem nuanced, and could just be a matter of semantics, but they set the stage for how success gets measured, and what kinds of expectations all parties bring when a psychopharmacotherapy is undertaken.
Knowingly or otherwise, clinicians who prescribe psychotropic medications must consider a multitude of factors, both biological and nonbiological, for judging drug effects; and, before that, deciding what, when, how, and for whom to prescribe any agent. Good psychopharmacology reflects such an awareness, and at its best, carries as prerequisite a systematic diagnostic assessment, appreciation for relevant dimensions of psychopathology, and the “fit” between symptom profiles and pharmacodynamic properties, as well as economy of scale (as when one drug accomplishes more than one goal), avoidance of redundant or unnecessary or ineffective agents, and ultimately, customer satisfaction.
Consider the fit between prescribed medications and clinical phenomenology in Clinical Vignette 1.1.
James was a 24-year-old information technologist who carried diagnoses of bipolar disorder, attention deficit disorder (ADD), stimulant (cocaine) use disorder, cannabis use disorder, nonverbal learning disability, generalized anxiety disorder, and a mixed personality disorder involving narcissistic and histrionic traits. His extensive medication history has included a multitude of drugs from virtually all major classes and combinations over the years, including anticonvulsants, antidepressants, antipsychotics, benzodiazepines, and psychostimulants. During his most recent consultation, the psychiatrist whom he saw reviewed his lengthy medication history, sought to identify which medications he had never taken, and picked lithium largely because it was one of the few medications James had never tried. He now presents for follow-up noting that “the lithium isn’t working.”
James’s case illustrates the kind of litany of problems that often afflict real-world patients. First, one must filter a plethora of psychiatric phenomena ranging from trouble with mood and anxiety to illicit substances to cognitive complaints, all colored by suspected personality characteristics; then, a vast historical pharmacopoeia requires a better understanding – what medications, at what doses, for how long, with what intended symptom targets, and with what observed effects? And, how accurate is the subjective recall of those parameters? Patients with multiple diagnoses pose especially difficult challenges, not simply because of the need to parse transdiagnostic overlapping symptoms (such as inattention due to bipolar disorder versus ADHD, or apathy due to depression versus cannabis abuse), but also because clinical improvement may demand a hierarchical approach to treatment (e.g., detoxification and abstinence as prerequisites for identifying and targeting primary mood symptoms). Lastly, complex cases sometimes invite the strategy employed here of sifting through a lifetime medication history in order simply to find a drug previously untried that is remotely pertinent to any of the key complaints and/or presumptive diagnoses – followed by the dismay of yet another failure.
A logical and systematic approach to appropriate pharmacotherapy in this case, as in any, begins with a careful and sometimes painstaking reassessment of the presenting phenomena and their context, including the chronology of symptoms, their longitudinal course over time, a careful interview to establish the presence or absence of distinct symptom constellations, episodes versus “usual” states, and the criteria by which categorical diagnoses are formulated. Knowledgeable collateral historians are often helpful sources of corroborative information, although their input too may require filtration and their face value cannot necessarily be taken for granted (as when judging the biases of an estranged, resentful, or otherwise dissatisfied partner or other family member). In James’s case, declaring lithium a “failure” assumes that his ailment – the object of treatment – conforms to a symptom picture for which lithium renders a known benefit (such as lithium-responsive bipolar disorder, or at least, impulsive aggression, or suicidal behavior) – lest its selection reflect merely an otherwise random choice based on the hearsay of previous diagnoses that may or may not be correct.